For nearly a century, immunologists have confronted the perplexing problem of how the immune system coexists harmoniously with the self, and for the great majority of this period, the conclusion was that it avoided all reactivity with self-molecules. Most recently, structural analysis of the T cell receptor, molecules produced by the major histocompatibility complex, and detailed information on gene rearrangement, coupled with cellular/genetic analysis using flow cytometry and transgenic animals, have provided the tools for a revolutionary reexamination of this central issue. There has been an explosion of information within the last 2 to 3 years on this topic, and the following issues (and findings) have received intense experimental scrutiny: a) The learning of self during ontogeny (positive selection governed by self-MHC molecules and the recognition of self-Ig and T-cell receptors); b) Mechanisms of self tolerance (negative selection by clonal deletion in the thymus; induction and propagation of clonal anergy in peripheral T and B cells; c) Modulating dangerous autoreactivity (monoclonal antibodies to TcR or MHC determinants; peptide inhibition of binding of self-molecules to MHC; TcR-peptide induction of regulatory T cells); d) Paradoxical self-reactivity (multispecific antibodies, idiotypic connectivity, heat shock protein association with autoimmunity, etc.). This meeting will be convened with the goal of helping to facilitate the emergence of a molecular basis for self-non-self discrimination. This could have direct repercussions on such crucial problems as autoimmune disease, infectious disease (mimicry of self by parasites), and the regulation of immune reactivity.